Smallpox is a serious, highly contagious, and frequently fatal infectious disease for which there is no specific treatment, and for which the only prevention is vaccination. Two clinical forms of smallpox have been described variolaminor and variola major, with the variola major form of smallpox being the more common and severe. There are four types of variola major smallpox: ordinary (the most frequent); modified (mild and occurring in previously vaccinated persons); flat; and hemorrhagic. Overall, variola major has a case-fatality rate of about 30%.
The most virulent form of smallpox, hemorrhagic smallpox, destroys the linings of the throat, stomach, intestines, rectum, and vagina and causes black, unclotted blood to ooze from the mouth and other body orifices. Because hemorrhagic smallpox has a much shorter incubation period than other forms of smallpox, it is likely not to be initially recognized as smallpox when first presented to medical care. As such, most victims die prior to a correct diagnosis, often before they are quarantined. Smallpox vaccination also does not provide much protection, if any, against hemorrhagic smallpox since hemorrhagic smallpox causes death of 94% of vaccinated patients. Hemorrhagic smallpox causes death in 99% of unvaccinated patients.
Because of the deadliness of smallpox, biological weapons, or so called “weapons of mass destruction” that are based on the etiological agent that causes smallpox, variola virus, are currently thought to be a great threat. Accordingly, there is an urgent need for methods and compositions for treating and preventing smallpox.
However, despite intense research, the primary treatments and preventions for smallpox are either not effective or not practical in the event of an outbreak from a virulent strain of smallpox.
The primary therapeutic tools for the control and eradication of smallpox include a live virus vaccine to prevent disease, and a vaccinia immune globulin (VIG) to treat disseminated infections.
The smallpox vaccine (live vaccinia virus) has many side-effects including: adverse reactions, scarring, ocular autoinoculation, myocardial infarction and dissemination in immunocompromised persons. Cell culture-derived vaccines, are being developed; however, these vaccines are also live viruses and pose many of the same drawbacks that plague the current vaccine. Accordingly, the public at large, the healthcare community and the military have been resistant to smallpox vaccinations because the risks of side-effects appear to outweigh the advantages. Further, as discussed above, current vaccination methods are practically ineffective against hemorrhagic smallpox or its derivatives, the agents that would most likely be used in biological weapons.
The existing vaccinia immune globulin products are derived from human donors who have been vaccinated with vaccinia virus (the vaccine for smallpox). As with all human products, the existing VIG must be tested exhaustively for blood borne human pathogens such as human immunodeficiency virus and hepatitis B. Therefore, the existing VIG suffers from several drawbacks including the necessity for using human volunteers, i.e. the use of a live virus as an immunogen which could cause infectious lesions that scar in healthy individuals and severe disseminated life-threatening infection in immunocompromised individuals. And, despite continuous screening of the donor population to assure consistency which is very expensive, product lots can vary significantly between batches and geographic regions.
Accordingly, the primary treatment for smallpox infection is not practical in most situations. In addition, since vaccinia virus is an ineffective vaccine for hemorrhagic smallpox, it is unlikely vaccinia immune globulin products will be effective against hemorrhagic smallpox.
Research into the biology of smallpox is intensive. For example, the genome of variola virus has been sequenced, and it is about 185 kbp in length and is predicted to contain over 200 proteins. Many proteins involved in transcription and DNA replication, and about 30 proteins that form the core and membrane components of virus particles have been identified. Other viral proteins have been identified that are thought to interact with host components to facilitate virus dissemination, prevent apoptosis, and attenuate immune responses. However, although well over 10 years have passed since the genome of vaccinia virus was sequenced, the biochemical function of most viral proteins, in particular, p28, which has been shown to be required for viral pathogenesis, remain elusive. The development of anti-viral assays and the discovery of effective drugs to combat smallpox infection have been slow.
Accordingly, despite great effort and the ever-present threat of a serious hemorrhagic smallpox outbreak, an effective, practical therapy (including prevention and treatment) for smallpox, is not currently available. Accordingly, there is a great need for new assays to discover drugs for the treatment of smallpox, and a great need for new smallpox therapies, particularly those that may be deployed rapidly, safely and in great number. This invention meets this need, and others.
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